ACTION LEVELS: WHAT ARE THEY, HOW DO THEY WORK AND WHERE DO THEY FIT INTO “FREE-FROM”

1. ACTION LEVELS: WHAT ARE THEY, HOW DO THEY WORK AND WHERE DO THEY FIT INTO “FREE-FROM” FDIN FreeFrom Grocery and Foodservice Summit, Daventry 18-19 September 2013 René Crevel

2. Outline • Background: setting the scene • Some definitions • Establishment of Reference Doses and Action Levels • VITAL 1.0 and VITAL 2.0 • ILSI Thresholds to Action Levels • Free-From and Action Levels • Conclusions

3. Why we need action levels • Food allergy is a food safety risk that needs to be managed • When used as ingredients, legislation requires allergens to be declaredBUT • Allergens can also be present inadvertently • How do we manage that risk and protect allergic consumers effectively?

4. Some definitions • Action level: concentration of allergen in a food below which the risk of a reaction is deemed insignificant. • Reference Dose: amount of allergen which is used to calculate the action level i.e. the dose at which the risk is deemed insignificant. • Threshold (biological): a dose level below which no (allergic) reactions occur

5. risk • Fundamental principle of toxicology: • “The dose makes the poison”(Paracelsus, 15th Century) • Implication: the key parameter is risk not hazard • Risk • the likelihood that, under particular conditions of exposure, an intrinsic hazard will represent a threat to human health. • Risk = f (hazard, exposure)with a consideration of the nature of the effects

6. Reference doses, Action levels and risk Risk = f (hazard, exposure)with a consideration of the nature of the effectsTo reduce the risk • We can’t consistently modify the hazard, but • We can modify the exposure • By reducing the dose • By reducing the number of susceptible people using the product

7. Managing Food allergens as a food safety issue • Eliminate unintended allergens? • the ultimate dose reduction • But what is absence? • “Zero is a very low number” (Steve Taylor, FARRP, University of Nebraska) • Gluten-free: 1981<500ppm; 2008 <20ppm • but 20ppm is NOT a No Effect Level • Reduce number of susceptible people exposed? • Precautionary (“may contain”) labelling?

8. …… Precautionary (advisory – “may contain”) labelling • Introduced in the 1990s • First suggested by CFIA/Health Canada • Voluntary • Very high level of precautionary labelling in some food categoriesBUT • No clarity about standards for application: use dependent on internal company standards and perception of risks • Negative perception by consumers and health care practitioner • Result: misunderstanding and mistrust, lack of observance and consequently higher risks to allergic consumers 10 Annex II foods 1 Annex II food

9. 100 100 Risk Profile 75 Observance of precautionary labelling (%) 75 Proportion of products affected (%) 50 25 50 0 0.1 1 10 100 Reference dose The dilemma: Precautionary labelling and risk ..we believe that we should set a gluten threshold level for “gluten free” labeling that best assists most individuals with celiac disease in adhering life-long to a “gluten-free” diet without causing adverse health consequences. … ..moving to a definition of “gluten-free” that adopts a criterion that is much lower than < 20 ppm gluten could have an adverse impact on the health of Americans with celiac disease.(US FDA)

10. so, Precautionary (advisory) labelling… • … on its own is not a definitive answer • needs standards to ensure consistent application • needs to communicate clearly the risk message to allergic consumers • needs to be used sparingly if it is to retain credibility and effectiveness • Current implementation doesn’t do this

11. legislators are aware of the issue… • Regulation 1169/2011. Chapter V. Article 36 • “3. The Commission shall adopt implementing acts on the application of the requirements referred to in paragraph 2 of this Article to the following voluntary food information: • (a) information on the possible and unintentional presence in food of substances or products causing allergies or intolerances;”

12. New allergen information requirements (Reg 1169/2011) • Precautionary labelling remains voluntary (Article 36) • However mandatory requirements are introduced (e.g. name of allergenic food) • Specific rules apply: “2. Food information provided on a voluntary basis shall meet the following requirements: (a) it shall not mislead the consumer, as referred to in Article 7; (b) it shall not be ambiguous or confusing for the consumer; and (c) it shall, where appropriate, be based on the relevant scientific data.”

13. So we really do need thresholds for food allergens, but how do we establish them?

14. Probability of no or slight effect Food Allergens: dose is critical Probability of severe effect Pollen-Food syndrome: Lip tingling, Itch Cardio-respiratory symptoms, severe angioedema, anaphylaxis Nausea, vomiting, shortness of breath Rash, hives INCREASING DOSE

15. Food allergens: challenge dose and distribution of population responses LOAEL: 0.5mg ED10

16. Characterising the hazard: approaches • Europrevall Workshop (Madrid, 2007) • Three possible approaches • Safety assessment approach (e.g. VITAL 1.0) • Establish LOAEL and NOAEL from clinical studies • Apply Uncertainty Factor(s) to get regulatory/management threshold • Benchmark dose approach(e.g. VITAL 2.0, ILSI) • Derive Benchmark dose from dose-distribution data • Based on toxicological models, this could be lower 95% confidence limit of ED10 or ED5 • Use as point of departure (PoD) for calculation of margin of Exposure (MoE) • Probabilistic modelling approach • Dose distribution modelling combined with modelling of other variables including allergen presence, allergen content, probability of consumption by allergic individuals, etc

17. Voluntary Incidental Trace Allergen Labelling (VITAL) • Originally launched in Australia in 2007 as a voluntary approach by industry to limit use of precautionary labelling • Action levels derived from US-FDA Threshold Working Group report (2006) using a safety assessment approach • Generated great interest across the world : NL, USA, etc Green: no precautionary labelling needed Yellow: precautionary labelling Red: label as ingredient

18. SEAC Voluntary Incidental Trace Allergen Labelling (VITAL) v2.0 • Comprehensive review of VITAL • Base the VITAL grid (action levels) on assessment and evaluation by recognised and independent international external experts • Allergen Bureau invited Prof Steve Taylor (FARRP, University of Nebraska) to form and chair a Scientific Expert Panel to review the VITAL grid

19. SEAC VITAL Scientific Expert Panel:Modus operandi • Keep original VITAL design principles: • Applies to foods for normal consumption • Not designed for “specific allergen-free” foods • Not designed for extremely reactive • Although would provide protection in many cases • Derive reference doses using dose distribution modelling • Level of protection • Panel decided to • Use ED01 where possible as the basis for reference doses, providing a minimum protection factor of 99% • Use lower 95% CI of ED05 where data were insufficient to use ED01 • Aim to protect vast majority against mild objective reactions

20. SEAC Data selection criteria • Criteria for inclusion: • Published studies or unpublished clinical data • Allergy confirmed by history or other factors • Double Blind Placebo Controlled Food Challenge (DBPCFC) • Description of NOAEL and/or LOAEL (or can determine from dosing regime) • Data on individual patients • Objective symptoms @ doses or history and subjective symptoms at the last dose • Criteria for exclusion • High starting doses and significant numbers of first-dose reactors

21. Allergens analysed by Vital Scientific Expert Panel Assembled and evaluated clinical data on almost all priority allergenic foods on the EU list Peanut Milk Egg Hazelnut Lupine Sesame seed Shrimp Celeriac/celery Fish Soybean Wheat Cashew Mustard No data at all: Molluscs

22. SEAC Allergen Threshold Studies • The accuracy of threshold estimates depends upon the population sampled, the number of subjects, and the statistical approach used. • Dose-distribution models were constructed using interval-censoring survival analysis (as described in Taylor et al., 2009). • Permitted inclusion of left- and right-censored observations which are excluded from other models • Facilitated the use of data generated using different protocols

23. SEAC ED 01 Peanut dose distribution: Adults and Children combined

24. VITAL Scientific Expert Panel Recommendations and Proposed Action Levels.

25. SEAC What do these reference values mean? The clinical data (1) “Anaphylaxis developed at a cumulative dose of peanut of 0.02g to 11.7g” (i.e. from 5mg to 2750mg of peanut protein) VITAL 2.0 Reference dose for peanut is at least 25-fold lower than the lowest dose to provoke an anaphylactic reaction

26. SEAC What do these reference values mean? The clinical data (2) 8 – 37 mg of peanut protein (32 – 148 mg of whole peanut)

27. What do these reference doses mean? The clinical data (3) • 24 patients • Dose escalation: 0.05mg to 2286mg peanut protein • Only small percentage of mild reactions up to 0.4mg peanut protein • 6662 doses delivered, 1023 symptoms recorded, 3% severe, • no severe symptoms below 25mg peanut protein • 869 children challenged • Starting doses 3 - 5mg protein for cows’ milk, wheat, soy, hen’s egg • 8-10% first dose reactors for milk and hen’s egg • 0.5 - 1% at risk of severe reactions • starting doses were 33 and 166-fold higher than VITAL Reference Doses for milk and egg respectively

28. The VITAL reference values, also adopted by the ILSI Expert Group “Thresholds to Action Levels” provide a high level of protection to allergic consumers: will protect a minimum of 95-99% of allergic consumers against mild objective reactions reactions in the more sensitive individuals are likely to be mild, transitory objective reactions typically requiring no pharmacological intervention They are transparent and can be used to communicate risk meaningfully to allergic consumers and health care practitioners They provide a consistent standard for precautionary labelling across industry, which can drive Improved allergen management Improved consumer safety Conclusions of the VSEP

29. SEAC MOVING FOrward • The ILSI-Europe Food Allergy Task Force Expert Group “Thresholds to Action Levels” • The ILSI “Thresholds to Action Levels” workshop Reading 13-14 September 2012

30. Conclusions endorsed by the workshop participants • A transparent set of reference doses (as a basis for action levels) would be a desirable outcome, in principle. • Data from food challenge studies provide the appropriate foundation from which these action levels can be derived • Sufficient data exist to move forward and better estimate the risk to the allergic population for the allergens specified in the report • The proposed reference doses, based on the work of the VITAL Scientific Panel, constitute a reasonable first pass to minimise risk to the allergic consumer while maintaining food choices

31. SEAC Action levels and “free-From” • Action Levels and Reference Doses are critical to the concept of “free-from”, but are they the threshold for “free-from” • NO, because they have been developed to apply to everyday foods, manufactured using everyday sanitation processes, etc • WHY? • The Reference Doses are NOT No Effect Levels • “Free-from” are specially prepared for and used by people who are at the very sensitive end of the spectrum and enhanced procedures need to be used to ensure that the risk remains low • However they can be used as a benchmark

32. Action levels and “free-from” “MAY CONTAIN” “NOT SUITABLE FOR” “FREE FROM” “SUITABLE FOR” ALLERGEN STATUS No mild reactions in the vast majority of highly sensitive allergic Individuals No reactions In the vast majority of allergic Individuals No severe reactions in the vast majority of allergic individuals PUBLIC HEALTH OUTCOME Manufacturing facility “IN CONTROL” Lower limit of analytical detection MANAGEMENT PARAMETER Action Level Allergen analytically absent to a high degree of confidence, GMPs to ensure absence of specific allergen Allergen management cross-contact control well-managed to a low level Allergen management controls managed, with unavoidable traces present despite efforts lower AMOUNT OF ALLERGENIC PROTEIN higher

33. Concluding remarks • The debate about Action Levels has focussed on the numbers • Allergic consumers do not understand them as proposed • They worry that they would make their life more dangerous. • In fact, Action levels agreed and accepted across industry should improve safety through • a consistent standard and approach • a common understanding of risk • Clear communication of that risk to allergic consumers, as well as to those who advise them (allergists, dieticians, etc). • This is a much better situation than the one we currently have, where the consumer cannot know how the risk posed by allergens has been assessed and mitigated • Implementation of harmonised Action levels, based on agreed and accepted Reference Doses, will enable food-allergic people to make safe choices with increased confidence.

34. Thank you for your attention